Oral GT-02287 Improves Fine Motor Skills in Mice

Gain Therapeutics presents study findings at international conference

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by Steve Bryson, PhD |

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Gain Therapeutics’ GT-02287, an oral candidate therapy for Parkinson’s disease, led to dose-dependent improvements in the health of nerve cells and fine motor skills in mice.

These findings, presented recently as a poster at the International Congress of Parkinson’s Disease and Movement Disorders 2022 in Madrid, add to a growing body of preclinical evidence that supports the therapy’s further development.

“We are especially excited by these latest data which expand on the accumulating preclinical evidence supporting the potential disease-modifying properties of our novel small molecule candidate, GT-02287,” Joanne Taylor, PhD, Gain’s senior vice president of research, said in a press release.

“If these results are supported in future clinical studies, GT-02287 could become an important first-in-class disease-modifying therapy for Parkinson’s disease,” added Taylor.

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GT-02287 is designed to increase the activity of beta-glucocerebrosidase (GCase), an enzyme that plays an essential role in the function of lysosomes — the cells’ recycling centers. A deficiency in GCase activity can lead to the toxic buildup of substances, including a protein called alpha-synuclein, which is thought to contribute to the nerve damage seen in people with Parkinson’s disease.

GT-02287 belongs to a class of molecules called small-molecule structurally targeted allosteric regulators (STARs). It was created by Gain’s Site-directed Enzyme Enhancement Therapy system, which uses the 3D structure of a target protein to predict how it may interact with potential therapeutics.

In previous preclinical studies, GT-02287 lowered the buildup of alpha-synuclein, eased inflammation, and lessened behavioral problems in animal models of Parkinson’s. In cell-based models, the therapy corrected several damaging abnormalities associated with Parkinson’s.

New preclinical data presented in the poster, “GT-02287, A Brain-penetrant Structurally Targeted Allosteric Regulator of Glucocerebrosidase Shows Evidence of Pharmacological Efficacy in Conduritol β-epoxide (CBE) Models of Parkinson’s Disease,” demonstrated GT-02287’s neuroprotective effects.

In a first study, researchers exposed rat neurons to CBE, a molecule that blocks the activity of GCase. Two different doses of GT-02287 then were added four or 24 hours later. After three days, nerve cell cultures were stained for a lysosome function marker, as well as for tyrosine hydroxylase, a marker of dopamine-producing neurons — the nerve cells that are progressively lost over the course of Parkinson’s.

GT-02287 treatment demonstrated a statistically significant, dose-dependent therapeutic effect by improving the overall health of lysosomes and neurites — projections from nerve cell bodies — such as axons or dendrites. Neurite degeneration also is a hallmark of Parkinson’s.

Follow-up study

In a follow-up behavioral study, mice were injected with alpha-synuclein in the striatum — the area of the brain that is typically damaged by Parkinson’s. CBE was administered daily for 15 days, and oral GT-02287 was given once a day for 14 days at doses of 30, 60, or 90 mg/kg.

The ability of mice to grasp and hang onto a wire were used to assess fine motor skills. Compared with untreated animals, GT-02287-treated mice showed statistically significant improvements in fine motor skills in a dose-dependent manner.

“Enhancement of lysosomal GCase activity by GT-02287 protects against key … hallmarks of [Parkinson’s disease], including neurite and lysosomal [disease], as well as locomotor deficits,” the researchers wrote. “Therefore, STARs therapy represents a novel pharmacological tool for the treatment of Parkinson’s disease, warranting further development towards the clinic.”

“Collectively, the body of preclinical data that has been generated is highly encouraging as it shows that GT-02287 may be able to intervene early in the disease process by restoring proper enzyme function and lysosomal health, thereby improving cell survival with the goal of ultimately halting disease progression,” said Gain Therapeutics’ Taylor.

This work was supported financially by The Michael J. Fox Foundation (MJFF) and the Silverstein Foundation for Parkinson’s with GBA.